This renewal International Cooperative Biodiversity Group (ICBG) application aims to discover and develop small molecule drug leads from cultured marine microbes and diverse coral reef organisms collected from Fiji and the Solomon Islands. Drug discovery efforts will focus on four major disease areas of relevance to the United States and low and middle income countries: infectious disease including tuberculosis and drug- resistant pathogens; neglected tropical diseases including hookworms and roundworms; cancer; and neurodegenerative and central nervous system disorders. Screening in these therapeutic areas will be performed in collaboration with two major pharmaceutical companies, two highly respected academic groups, and various testing centers and government resources that are available to facilitate drug discovery and development. The acquisition of source material for this program will be linked to biotic surveys, informed by ecological investigations addressing the chemical mediation of biotic interactions, and enriched using ecology- based strategies designed to maximize secondary metabolite production and detection. The program is heavily invested in microbial genomics, chemical ecology, the application of innovative cultivation methods and bioassays, sequence-based methodologies, and modern molecular and analytical tools as methods to improve the efficiency with which new natural products are discovered. The structures of all new compounds will be solved using modern techniques in analytical chemistry and produced in sufficient quantities for pre-clinical evaluation. The research activities of the four associate programs (AP1-4) are highly synergetic and emphasize training and technology transfer to the host country. The research maximizes the expertise of the program leaders to generate collaborative and highly interdisciplinary research objectives that transcend traditional natural product drug discovery paradigms. These activities are coordinated through the Central Operations Core and facilitated by the South Pacific Center for Drug Discovery and Conservation. The CDDC will work with marine ecologists to develop more effective strategies for reef conservation and to expand the Locally-Managed Marine Area (LMMA) program, which has proven to be a highly effective method to bring village-level awareness to the importance of conservation and the maintenance of healthy coral reefs.